Helmholtz Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany.
German Center for Diabetes Research, Helmholtz Zentrum München, Neuherberg, Germany.
Diabetes. 2017 May;66(5):1247-1257. doi: 10.2337/db16-1088. Epub 2017 Feb 7.
In pancreatic β-cells, mitochondrial bioenergetics control glucose-stimulated insulin secretion. Mitochondrial dynamics are generally associated with quality control, maintaining the functionality of bioenergetics. By acute pharmacological inhibition of mitochondrial fission protein , we demonstrate in this study that mitochondrial fission is necessary for glucose-stimulated insulin secretion in mouse and human islets. We confirm that genetic silencing of increases mitochondrial proton leak in MIN6 cells. However, our comprehensive analysis of pancreatic islet bioenergetics reveals that does not control insulin secretion via its effect on proton leak but instead via modulation of glucose-fueled respiration. Notably, pyruvate fully rescues the impaired insulin secretion of fission-deficient β-cells, demonstrating that defective mitochondrial dynamics solely affect substrate supply upstream of oxidative phosphorylation. The present findings provide novel insights into how mitochondrial dysfunction may cause pancreatic β-cell failure. In addition, the results will stimulate new thinking in the intersecting fields of mitochondrial dynamics and bioenergetics, as treatment of defective dynamics in mitochondrial diseases appears to be possible by improving metabolism upstream of mitochondria.
在胰腺β细胞中，线粒体生物能学控制着葡萄糖刺激的胰岛素分泌。线粒体动力学通常与质量控制有关，维持生物能学的功能。通过急性药理学抑制线粒体裂变蛋白，我们在这项研究中证明，在小鼠和人类胰岛中，线粒体裂变对于葡萄糖刺激的胰岛素分泌是必要的。我们证实，MIN6 细胞中 的基因沉默增加了线粒体质子泄漏。然而，我们对胰腺胰岛生物能学的全面分析表明， 并不是通过其对质子泄漏的影响来控制胰岛素分泌，而是通过调节葡萄糖驱动的呼吸作用。值得注意的是，丙酮酸完全挽救了分裂缺陷的β细胞受损的胰岛素分泌，这表明线粒体动力学的缺陷仅影响氧化磷酸化上游的底物供应。这些发现为线粒体功能障碍如何导致胰腺β细胞衰竭提供了新的见解。此外，这些结果将在线粒体动力学和生物能学的交叉领域激发新的思考，因为通过改善线粒体上游的代谢，似乎可以治疗线粒体疾病中的缺陷动力学。
